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G Proteins 12. TRANSDUCTION MECHANISMS 12. TRANSDUCTION MECHANISMS G Proteins Katerina J. Damjanoska and Louis D. Van de Kar∗ 1. INTRODUCTION Receptors can be classified into three large classes: ligand gated ion channels; genotropic receptors, which can act as transcription factors; and G protein-coupled receptors (GPCRs). GPCRs are membrane proteins with a unique seven- transmembrane transversing structure (hepta-helix). GTP-binding proteins (G proteins) transmit extracellular signals from cell-surface receptors to intracellular effectors such as phospholipases, adenylyl cyclases, and ion channels. G proteins are a family of trimeric proteins, consisting of α, β, and γ subunits. The α subunits of G proteins bind guanine nucleotides (GTP and GDP) with high affinity and specificity (Dessauer 1996; Neer 1995). It is this affinity for guanine nucleotides that gives them their name G proteins. Approximately 1% of the mammalian genome encodes for G-protein coupled receptors (Morris 1999), and approximately 50% of pharmaceuticals target receptors, largely GPCRs (Drews 2000). Although no drugs have been developed, so far, that specifically act on G proteins, G proteins are potential pharmaceutical targets as changes in G proteins and their associated regulatory proteins have been implicated in a number of pathological conditions. Since the discovery of G proteins in the late 60’s and early 70’s of the 20th century, by Alfred G. Gilman and Martin Rodbell, research dedicated to the study of G proteins has increased dramatically. G proteins associate with a variety of receptors (See Table 1). This enables G proteins to be intracellular transducers of a variety of extracellular signals such as hormones, neurotransmitters, odorants, and ∗ Katerina J. Damjanoska and Louis D. Van de Kar, Ph.D., Center for Serotonin Disorders Research and Department of Pharmacology & Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, 60153 U.S.A. 289 290 K.J. DAMJANOSKA ET AL. photons. This chapter will provide an overview of the variety of G protein subtypes and their associated proteins. As this review will focus on psychiatric disorders, we will limit our discussion to the importance of G proteins in the central nervous system. 2. TYPES OF HETEROTRIMERIC G PROTEINS Heterotrimeric G proteins (Gαβγγ) are currently categorized according to the Gα subunit, historically thought to be the only active subunit of the G protein trimer. As there are four main types (classes or families) of Gα subunits, there are four main classes of heterotrimeric G proteins. The classes of Gα proteins, and hence of G protein trimers, are Gαs, Gαq, Gαi, and Gα12. Each class of Gα proteins has subtypes (See Section 2.2). Although multiple subtypes of Gα proteins have been identified, there are not as many Gα proteins as there are G protein-coupled receptors (GPCRs). Table 1 shows the different classes of Gα proteins and some of the receptors to which they are coupled. Many GPCRs couple to the same Gα protein subtype, yet are still capable of mediating their specific cellular and physiologic effects. This overlap in signal transduction proteins can be partially explained by differential expression of proteins in cells. Yet, there are numerous cells that express more than one GPCR and multiple subtypes of Gα proteins. One theory proposes that cellular microdomains with lipid-rich regions (lipid rafts) in the cell membrane preferentially aggregate the required and relevant proteins within close proximity of their respective receptors. Gα proteins and their effector enzymes can be localized to microdomains by their association with specific proteins of the membrane and cytoskeleton, such as tubulin (See Section 5) (Donati 2003; Huang 1997). Gα proteins can also undergo a variety of lipid modifications that may assist in targeting Gα proteins to subcellular compartments, caveolae, and lipid microdomains (See Section 5). Furthermore, not all Gα protein subtypes are 7 sequestered to the same microdomain. For instance, Gαq proteins are normally 7 found in caveolae without being associated to Gβγγ proteins. On the other hand, while Gαi and Gαs proteins can be found in caveolae, they are predominantly found in lipid rafts complexed to Gβγγ proteins (Oh 2001). The theory of cellular compartmentalization of the Gα proteins provides a plausible explanation for the speed of selection (efficiency) and selectivity of receptor-to-G protein signaling. Another emerging theory concerning receptor-to-G protein coupling is “agonist- directed trafficking of receptor stimulus” (Kenakin 1995). This theory suggests that ligands can induce different conformational changes in the receptor so that one receptor can activate multiple Gα protein-mediated signaling cascades (Kenakin 1995 ; Berg 1998). G PROTEINS 291 Table 1. Gα protein families and the receptors that are coupled to them. Some of the information reported in this table for receptor-G protein coupling is obtained from in vitro reconstitution or studies in cell culture and are not confirmed in vivo. The results obtained from reconstitution or cell culture studies must be taken with caution as the protein levels and ratios of purified or transfected receptors and G proteins may exceed the physiological levels of the proteins and result in otherwise unlikely interactions. These in vitro studies may also lack the associated proteins critical for the association between receptors and G proteins. Gα Protein Associated Receptors References Family Gαs Adenosine (A2A, A2B) 10, 11, 12, 13 Adrenergic [α2A, α2B, α2C (formerly α2C10, α2C2, α2C4), β1, β2, β3] 14, 15, 16, 17 Calcitonin (CTR) 18 Complement (C5A) 19 Corticotropin-releasing hormone (CRH-R1, -R1α, -R2) 20, 21 Dopamine (D1, D3, D5) 22 Endothelin (ETAR) 23, 24 Glucagon (GR) 25 Gonadotropin-releasing hormone (GnRH-R) 26 Histamine (H2) 27 Luteinizing hormone/chorionic gonadotropin (LH/CG R) 28 Melanocortin (MC1R, ACTHR, MC3R, MC4R, MC5R) 29 Parathyroid hormone (PTH) 30, 31 Prostaglandin (IP, EP2, EP4, DP, EP3B, EP3C) 32, 33 Serotonin (5-HT4, 5-HT6, 5-HT7) 34, 35, 36 Substance P (SPR or NK1R) 37, 38 Thyroid Stimulating Hormone (TSH) 39 Vasopressin (V2) 40 Gαi Adenosine (A1 and A3) 41, 42, 43 Adrenergic (α2A, α2B, α2C) 44, 17 Angiotensin (AT1) 45 Bombesin 46 Bradykinin (B1, B2) 47, 48, 49, 50 Calcitonin (CTR) 51, 52 Cannabinoid (CB1, CB2) 53, 54 Cholecystokinin (CCKB) 55 292 K.J. DAMJANOSKA ET AL. Table 1. (continued) Gα Protein Associated Receptors References Family Gαi Compliment (C3A, C5A) 56, 57, 58 Corticotropin-releasing hormone (CRH-R1α) 20 Dopamine (D1, D2S, D2L, D3, D4) 22 Endothelin (ETBR) 23, 24 Galanin (GALR1, GALR2) 59, 60 Glutamate (mGluR2, mGluR4) 61, 62 Gonadotropin-releasing hormone (GnRH-R) 26 Histamine (H3) 63 Insulin-like growth factor (IGF IR) 64 Luteinizing hormone/chorionic gonadotropin (LH/CG-R) 28 Lysophosphatidic Acid (LPA) 65 Melatonin 66, 67 Muscarinic acetylcholine (m2 and m4) 68, 69 Neuropeptide Y* (Y1, Y2, Y4, Y5) 70, 71 Neurotensin* (NTS1) 72, 73, 74 75, 76, 77, Opioid (*µ, *κ and *δ) 78, 79 Orphanin/Nociceptin (OFQR) 76 Oxytocin (OTR) 80, 81 Parathyroid hormone (PTH) 30 Platelet-activating factor (PAF) 82 Prostaglandin E (EP3A, EP3D, CRTH2) 83, 32, 33 Serotonin (*5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5- 34, 84, 85, HT5A) 35, 36 Somatostatin (SRIF) 86, 87 Substance P (SPR or NK1R) 37, 88 Thrombin 89 Thyroid Stimulating Hormone (TSH) 90 Gαz Compliment (C5a) 91 Dopamine (D2S, D2L, D3, D4, D5) 22 Formyl peptide (fMLP) 91, 92 Melatonin 66 93, 94, 95, Opioid (*µ, κ and δ) 77, 96, 78 G PROTEINS 293 Table 1. (continued) Gα Protein Associated Receptors References Family Gαz Serotonin (*5-HT1A) 97 Gαq Adenosine (A2A, A2B, A3) 98, 99, 41 Adrenergic (α1, α2A) 100, 101 Angiotensin (AT1) 102 Bombesin (GRP-R, NMB-R, BRS-3) 46, 103, 104 47, 48, 49, Bradykinin (B1, B2) 50 Calcitonin (CTR) 105 Cholecystokinin (CCKA, now CCK2; CCKB, now CCK1) 106, 55, 107 Compliment (C5A) 108 Corticotropin-releasing hormone (CRH-R1α) 20 Dopamine (D3) 109 Endothelin (ETAR, ETBR) 24 Galanin (GALR2) 59 Glutamate (mGluR1, mGluR5) 110, 111 Gonadotropin-releasing hormone (GnRH-R) 112, 113 Gαq Histamine (H1, H2) 27 (continued) Lysophosphatidic Acid (LPA) 114 Melanocortin (MC3R) 115 Muscarinic (m1, m5) 68, 116 Neurokinin (NK2) 117, 118 Neurotensin (NTS1) 73 Orexin (types 1) 119 Oxytocin 80 Platelet-activating factor (PAF) 82 Prostaglandin (TP, IP, FP, EP3D) 32, 33 Purinoceptor (P2Y) 120 Serotonin (5-HT2A, 5-HT2B, 5-HT2C) 34, 35, 36 Substance P (NK1R or SPR) 37, 121 Thrombin 122 Thyroid Stimulating Hormone (TSH) 39 Vasopressin (V1a, V1b) 104, 123 294 K.J. DAMJANOSKA ET AL. Table 1. (continued) Gα Protein Family Associated Receptors References Gα12 Adrenergic (α1) 124 Bombesin (GRP-R) 46 Endothelin (ETBR) 125 Galanin (GALR2) 59 Lysophosphatidic Acid (LPA) 126 Prostaglandin (TP) 32 Thrombin Receptor 127 Thyroid Stimulating Hormone (TSH) 90 * Denotes receptor/G protein interactions confirmed in vivo. Studies performed in vivo consisted of 1) receptor and Gα protein colocalization depicted by immunohistochemistry, 2) identification of the Gα protein family mediating the specific response by treatment with pertussis toxin or cholera toxin, or 3) in vivo suppression of expression of specific Gα proteins by antisense oligodeoxynucleotides. Abbreviations: CRTH2, chemoattractant receptor-homologous molecule expressed on T-helperpyp type 2 cells; EP, prostag- landin E (PGE22 ) receptor; IP, prostaglandin I (PGI22 ) receptor; DP, prostaglandin D (PGD 2 ) recep- tor; FP, prostaglandin F (PGF2α) receptor; TP, thromboxane (TXA2) receptor. 2.1.Regulation of G protein signaling Receptors are coupled to the trimeric form (αβγγ) of G proteins. When a receptor agonist binds to its receptor it induces a conformational change that increases the 2+ 2+ affinity of the Gα protein for Mg . Once Mg is bound to the Gα protein, it stimulates the release of guanine diphosphate (GDP) from the Gα protein, and the binding of guanine triphosphate (GTP) to the Gα protein, promoting the dissociation of the Gβγγ protein dimer from the Gα protein.
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